Pelabresib/Ruxolitinib Data Underscore Need for Novel End Points in Myelofibrosis Trials

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July 15, 2024

Author(s): Jax DiEugenio

Although a 35% reduction in spleen volume (SVR35) and a 50% reduction in total symptom score (TSS50) have been established as key end points in clinical trials evaluating therapies for the treatment of patients with myelofibrosis, integrating end points such as overall survival (OS) and progression-free survival (PFS) as key objectives in future studies could help guide drug development and measure any disease-modifying properties of treatments, according to Aaron Gerds, MD.

“[Findings] from [the phase 3] MANIFEST-2 [NCT04603495] and TRANSFORM-1 [NCT04472598] trials are a wakeup call for the field that we need to move beyond SVR35 and TSS50 [as clinical trial end points in myelofibrosis]. We have drugs that are good at making patients’ symptoms better; however, we need are drugs that truly modify the disease course in a meaningful way,” Gerds explained.

Updated data from the MANIFEST-2 presented at the 2024 ASCO Annual Meeting showed that patients with myelofibrosis who received frontline pelabresib (CPI-0610) plus ruxolitinib (Jakafi; n = 214) experienced an SVR35 rate of 65.9% at week 24 compared with 35.2% for those given ruxolitinib plus placebo (n = 216). Notably, updated data showed that in patients who experienced an SVR35 at any time, 13.4% of patients in the experimental arm lost that response vs 27.8% of patients in the placebo arm.1

Additionally, the TSS50 rates at week 24 were 52.3% for pelabresib plus ruxolitinib vs 46.3% for placebo plus ruxolitinib, translating to a numerical improvement that was not statistically significant (difference, 6.0%; 95% CI, –3.5% to 15.5%; nominal P = .216).

Notably, 40.2% of patients in the pelabresib arm experienced both SVR35 and TSS50 at week 24 compared with 18.5% of patients in the placebo arm.

In an interview with OncLive®, Gerds an assistant professor of medicine, Hematology, and Medical Oncology at Cleveland Clinic Taussig Cancer Institute in Ohio, detailed prior data from MANIFEST-2 presented at the 2023 ASH Annual Meeting;2 expanded on updated data presented at the 2024 ASCO Annual Meeting; and emphasized the need to look beyond current end points in clinical trials evaluating treatments for patients with myelofibrosis.

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Ropeginterferon alfa-2b shows anti-polycythaemia vera activity without causing clinically significant anaemia

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Keita Kirito, Albert Qin, Shanshan Suo, Rongfeng Fu, Daoxiang Wu, Toshiaki Sato, Oleh Zagrijtschuk, Kazuya Shimoda, Norio Komatsu & Jie Jin

July 11, 2o24

Polycythaemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) that, in most cases, harbour the Janus kinase 2 gene (JAK2) driver mutation JAK2V617F [1]. PV is characterised by an over-production of blood cells with increased haematocrit levels, which is a risk factor for thrombotic events (TEs) and cardiovascular mortality [1, 2]. Low-dose aspirin and phlebotomy are usually recommended for patients with low-risk PV (i.e., no history of thrombosis and age ≤60 years). The National Comprehensive Cancer Network (NCCN) recommends ropeginterferon alfa-2b (BESREMi®) as a preferred cytoreductive treatment for patients with low- or high-risk PV [3].

Ropeginterferon alfa-2b is a novel polyethylene glycol (PEG)-conjugated recombinant proline-interferon alpha (IFN-a) with a favourable in vivo pharmacokinetic (PK) profile [4, 5]. Ropeginterferon alfa-2b has demonstrated substantial anti-PV clinical activity, including complete haematologic response (CHR; defined as a haematocrit <45% without phlebotomy, a platelet count ≤ 400 × 109/L, and a white blood cell count ≤10 × 109/L) and a reduction in the JAK2V617F allele burden [6,7,8,9]. Ropeginterferon alfa-2b injection is approved for adult patients with PV at an initial dose of 100 µg (or 50 µg for patients already receiving cytoreductive therapy) with 50 µg incremental intrapatient increases in the dose up to a maximum recommended dose of 500 µg every two weeks. It can take several months to reach the plateau dose level [6]. An alternative dosing regimen with a higher starting dose of 250 µg and simpler intrapatient dose escalation to 500 µg every two weeks with flexible dose adjustment according to tolerability was explored as a treatment option. This regimen controlled PV effectively, as defined by the CHR, and was associated with a shorter time to achieve a CHR [8, 9]. In this report, we aimed to examine the data from the approved slow-dose titration and exploratory higher starting dose regimens focusing on the dynamics of haemoglobin (Hgb) and the occurrence of anaemia. Anaemia is important in the context of PV treatment for several reasons. First, patients who undergo frequent phlebotomy may suffer from symptomatic iron deficiency, leading to anaemia [10]. Anaemia and symptoms can negatively affect the patient well-being and should be avoided in patients with PV and MPNs. The symptoms include headache, insomnia, concentration difficulties, dizziness, restless legs and may coincide and potentiate the disease-related symptoms of the underlying MPN [11,12,13]. Commonly used agents in the PV treatment cause anaemia in substantial numbers of cases ranging from 18% with hydroxyurea (HU) [14] to 72% with ruxolitinib [11, 15]. Anaemia is symptomatic in many cases and may limit the treatment dose or lead to treatment interruption if uncontrolled or severe cases are present. Association between venous thromboembolism and iron-deficiency anaemia has also been shown [16]. Thus, having an agent that can effectively control the elevated haematocrit without excessively suppressing the normal erythropoiesis is a major therapeutic advantage.

An important question regarding ropeginterferon alfa-2b in this context is whether the control of haematocrit is commonly accompanied by clinically significant anaemia, i.e., at the ≥grade 3 level or at the moderate, grade 2 level, but the anaemia is persistent and unmanageable. We therefore performed a retrospective analysis of the effect of ropeginterferon alfa-2b on Hgb levels at various time points or on the occurrence of anaemia with the data available from our two prospective clinical studies in patients with PV.

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Risk of myeloproliferative neoplasms among U.S. Veterans from Korean, Vietnam, and Persian Gulf War eras

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July 18, 2024

Andrew Tiu, Zoe McKinnell, Shanshan Liu, Puneet Gill, Martha Antonio, Zoe Shancer, Nandan Srinivasa, Guoqing Diao, Ramesh Subrahmanyam, Craig M. Kessler, Maneesh Jain

Abstract

The Promise to Address Comprehensive Toxics (PACT) Act expanded U.S. Veterans’ health care and benefits for conditions linked to service-connected exposures (e.g., Burn Pits, Agent Orange). However, myeloproliferative neoplasms (MPN) are not recognized as presumptive conditions for Veterans exposed to these toxic substances. This study evaluated the development of MPN among U.S. Veterans from the Korean, Vietnam, and Persian Gulf War eras. This retrospective cohort study included 65 425 Korean War era Veterans; 211 927 Vietnam War era Veterans; and 214 007 Persian Gulf War era Veterans from January 1, 2006, to January 26, 2023. Veterans with MPN, thrombosis, bleeding, and cardiovascular risk factors were identified through ICD-9 and -10 codes. Veterans from the Persian Gulf War era had the highest risk of developing MPN compared with Veterans from the Korean and Vietnam War eras, hazard ratio (HR) 4.92, 95% confidence interval (CI) 4.20–5.75 and HR 2.49, 95% CI 2.20–2.82, both p < .0001, respectively. Vietnam War era Veterans also had a higher risk of MPN development compared with Korean War era Veterans, HR 1.97, 95% CI 1.77–2.21, p < .0001. Persian Gulf War era Veterans were diagnosed with MPN at an earlier age, had higher risks of thrombosis and bleeding, and had lower survival rates compared with Korean War and Vietnam War era Veterans. This study reinforces evidence that environmental and occupational hazards increase the risk of clonal myeloid disorders and related complications, impacting overall survival with MPN. Limitations include the inability to confirm clonality and fully verify deployment and exposure status.

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Immunofluorescence microscopy on the blood smear identifies patients with myeloproliferative neoplasms

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July 17, 2024

Carlo Zaninetti, Leonard Vater, Lars Kaderali, Carl C. Crodel, Tina M. Schnöder, Jessica Fuhrmann, Leonard Swensson, Jan Wesche, Carmen Freyer, Andreas Greinacher & Florian H. Heidel

Myeloproliferative neoplasms (MPN) are a group of clonal stem cell disorders with heterogeneous clinical presentation [1]. Due to the risk of severe thromboembolic complications and disease progression, the early recognition of an MPN prior to the appearance of clinical complications is clearly warranted to facilitate early pharmacologic intervention [2,3,4]. Detection of the somatic mutations by genotyping has become an essential part of the diagnostic work-up of suspected subjects, as well as of the risk stratification after the diagnosis of MPN has been confirmed [5]. However, in many parts of the world molecular testing is barely affordable.

We have established an immunofluorescence microscopy (IF)-based method for platelet phenotyping on the peripheral blood smear [6]. This method has been proven to be highly efficient in the diagnosis of diverse hereditary platelet disorders by recognizing disease-specific changes of cell structures, including alterations of leukocytes and red blood cells (RBC) [7, 8]. Major advantages of this approach are the need of small amounts of blood (<100 μL) and the possibility to send the blood films by regular mail even long distances.

It is well-known that morphology of peripheral blood cells is also often altered in MPN [9, 10]. However, due to different methods and the heterogeneity of the patients’ populations, results are difficult to compare.

In the present study, we aimed at assessing platelet phenotype using our IF method in a cohort of patients diagnosed with MPN. The study has been registered in the German Clinical Trials Register (DRKS-ID: DRKS00032588). Three German reference centers for diagnosis and treatment of MPN took part in the study: Internal Medicine C, University Medicine Greifswald; Internal Medicine 2, University Hospital Jena; and Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Germany. The study protocol was approved by the institutional review boards of all centers. Patients or their legal guardians signed written informed consent to the investigation, which was conducted according to the Declaration of Helsinki. Healthy controls were enrolled among blood donors at the Institute for Transfusion Medicine, University Medicine Greifswald, Germany.

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Dr Klisovic on the Early Use of JAK Inhibitors in Younger Patients With Low-Risk Myelofibrosis

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July 15, 2024

Author(s): Rebecca Klisovic, MD

Rebecca Klisovic, MD, chief medical information officer, University Hospitals Seidman Cancer Center, discusses a case study featuring a patient with newly diagnosed myelofibrosis and reviews the optimal JAK inhibitor–based treatment regimen for this patient, as determined by a panel of oncologists at an OncLive® State of the Science Summit™ on hematologic malignancies.

This case study featured a 40-year-old male patient with newly diagnosed myelofibrosis, Klisovic begins. She notes that the discussion about this patient was interesting discussion because the patient was young with low-risk disease. The panel’s conversation centered around the early use of the JAK inhibitor ruxolitinib (Jakafi) to potentially improve this patient’s overall survival outcome, Klisovic details.

Ruxolitinib has demonstrated superiority over placebo and best available therapy in the phase 3 COMFORT-I (NCT00952289) and COMFORT-II studies (NCT00934544). However, it was noted in the conversation that this patient would not have qualified for enrollment in the COMFORT studies due to his low-risk disease status, Klisovic explains. This led to a debate about the appropriateness of initiating treatment earlier rather than later, even in patients who may not otherwise require immediate therapy, according to Klisovic.

Another key question raised was whether ruxolitinib is truly disease-modifying, particularly in a younger patient, Klisovic says. This is a crucial consideration because the long-term benefits of a therapy and its potential for altering the disease course are significant factors in deciding early intervention, she expands.

Additionally, there was a strong recommendation to monitor this patient closely for transplant potential given his age, Klisovic continues. Although this patient’s molecular profile was not presented, discussants highlighted molecular stratification as an important factor for guiding treatment decision-making in similar cases, she states. Klisovic adds that the identification of higher-risk mutations could alter the treatment trajectory and influence whether early intervention or watchful waiting is more appropriate.

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Prognostic Scores Validated for Additional Mutations in Secondary Myelofibrosis

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July 11, 2024

An article in the American Journal of Hematology reported an in-depth characterization of clinical and molecular differences between primary and secondary myelofibrosis (MF). Researchers also found that two newer prognostic scores, the Mutation-Enhanced International Prognostic Scoring System 70 (MIPSS70) and MIPSS70+ v2.0, stratified risk in patients with secondary MF more accurately than the myelofibrosis secondary to polycythemia vera and essential thrombocythemia prognostic model (MYSEC-PM). These two scores also are the first to account for additional mutations besides SRSF2 status in patients with secondary MF.

Several prognostic scores have been developed for patient risk stratification and appropriate treatment allocation in primary MF. These include the IPSS, Dynamic IPSS (DIPSS), and DIPSS-plus. Studies have highlighted the prognostic significance of molecular alterations in primary MF, particularly mutations in High Molecular Risk (HMR) genes such as ASXL1, EZH2, IDH1/2, SRSF2, and U2AF1. Consequently, these genetic and molecular alterations were incorporated into the latest prognostic scores, including MIPSS70, MIPSS70-plus, and MIPSS70+ v2.0.

“As opposed to primary MF, few studies explored mutations prognosis significance in secondary MF,” explained Matteo Guerra and colleagues. “The MYSEC-PM was specifically developed for secondary MF and displays a more accurate prognostic performance than IPSS and DIPSS. However, no molecular prognostic models accounting for additional mutations in SMF have yet been described.”

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Observational MOST Trial Reveals Progression Trends in Low-Risk Myelofibrosis

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July 11, 2024

Author(s):Jax DiEugenio

Findings from the prospective, observational MOST trial (NCT02953704) showed that 58.5% of patients with low- or intermediate-1–risk myelofibrosis enrolled in cohort A (n = 205) met at least 1 criterion for disease progression after a median follow-up of less than 53 months, which was a higher rate than investigators expected, according to Aaron Gerds, MD.

Cohort A included patients with low-risk or intermediate-1–risk disease, where patients were considered to have intermediate-1–risk myelofibrosis based on age only. Cohort B (n = 27) featured patients with intermediate-1–risk disease with other Dynamic International Prognostic Scoring System (DIPSS) risk factors beyond age.

Findings presented at the 2024 EHA Congress showed that of the 120 patients in cohort A who experienced disease progression, 64 (53.3%) met 1 criterion for progression, 27 (22.5%) met 2 criteria, and 29 (24.2%) met at least 3 disease progression criteria. The most common progression criteria met in cohort A included a hemoglobin level of less than 10 g/dL (47.5%) and a platelet count of less than 100 x 109/L (31.7%). For Cohort B, 25 patients (92.6%) met 1 progression criterion, 1 patient (3.7%) met 2 progression criteria, and 1 patient (3.7%) met 3 progression criteria.

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Myelofibrosis management in routine clinical practice with a focus on patients with cytopenias: recommendations from a global consensus group

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Steffen Koschmieder, Prithviraj Bose, Martin H. Ellis, Vikas Gupta, Jean-Jacques Kiladjian, John Mascarenhas, Vikram Mathews, Francesco Passamonti & Claire Harrison

Leukemia (2024)

Myelofibrosis (MF) is a Philadelphia chromosome (BCR::ABL1)-negative myeloproliferative neoplasm, a hallmark of which is progressive deposition of fibrotic tissue in bone marrow [1]. Clinical manifestations of MF often include splenomegaly, cytopenias (such as severe anemia), and extramedullary hematopoiesis [1]. The Janus kinase inhibitor (JAKi) therapies ruxolitinib (RUX) and fedratinib (FED) have demonstrated significant clinical efficacy in splenic volume reduction and symptom improvement, but they may induce treatment-related anemia and thrombocytopenia [2,3,4,5,6,7,8,9]. Other JAKi options include pacritinib (PAC), which received FDA approval in 2022 for patients with MF and severe thrombocytopenia (platelet count <50 × 109/l), and momelotinib (MMB), which received FDA and EMA approval in 2023/2024, respectively, for patients with MF and anemia [10,11,12]. Clinical trials with JAKis in MF are summarized in reference [1].

National and international guidelines exist for the management of MF; however, a need remains for practical guidance applicable in everyday clinical practice, especially for patients experiencing cytopenias or potential failure of current therapy. The landscape is further complicated by the availability of multiple prognostic tools for MF; as such, clinicians may find disease prognostication challenging and confusing. Additionally, to maximize clinical applicability of trial data, inclusivity of eligibility criteria in the context of the real-world MF patient population should be considered.

Recognizing these significant challenges, an international expert consensus group was established to provide best practice recommendations for healthcare professionals, intending to supplement, but not replace, existing guidelines.

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Mascarenhas on the SENTRY Trial Design and Goals

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J

By John Mascarenhas, MD

John Mascarenhas, MD, professor, medicine, Icahn School of Medicine, Mount Sinai, director, Center of Excellence for Blood Cancers and Myeloid Disorders, member, The Tisch Cancer Institute, Mount Sinai, discusses the methods, design, and inclusion criteria of the phase 3 SENTRY trial (NCT04562389) for patients with JAK inhibitor treatment-naive myelofibrosis.

SENTRY is a global, multicenter, phase 1/3 study where investigators are assessing the efficacy and safety of selinexor (Xpovio) combined with ruxolitinib (Jakafi) in this patient population.

According to Mascarenhas, the primary end points of phase 3 of the trial include the proportion of patients with spleen volume reduction of greater than or equal to 35% at week 24 (SVR35), and the proportion of patients with a total symptom score reduction of greater than or equal to 50% at week 24 (TSS50), as measured by the myelofibrosis symptom assessment form V4.0.

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Ph- MPN in Adolescent and Young Adult Patients

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June 26, 2024

Elizabeth L. Courville, MD

England JT, Szuber N, Sirhan S, et al. Clinical features and long-term outcomes of a pan-Canadian cohort of adolescents and young adults with myeloproliferative neoplasms: a Canadian MPN group study. Leukemia. 2024;38(3):570-578.

The classical BCR:: ABL1-negative myeloproliferative neoplasms (Ph- MPNs) polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are typically diseases of older adults, with a median age at diagnosis within the sixth decade of life. In two large case series from cancer centers in the United States, adolescent and young adult (AYA) patients were reported to account for 11 to 12% of the Ph- MPNs evaluated.1,2  The data on AYA patients with Ph- MPNs is less robust than that available for their older counterparts, and this patient population may not be represented in cohorts used to develop prognostic scoring systems.

Recently, James T. England, MD, MSc, and colleagues investigated the clinical features and long-term outcomes of a cohort of 609 patients (17 pediatric patients aged <18 years and 592 patients aged 18-45 years) with Ph- MPNs from across eight participating centers in Canada. Initial diagnoses are shown in Figure 1. Clinical features from the current study cohort are compared with those of a 2018 Mayo Clinic AYA cohort1  (Table). The patients were diagnosed between 2000 and 2022, with MPN driver mutation analysis performed in 89% and next-generation sequencing (NGS) of clinically relevant myeloid genes performed in 48%. More than one-third of patients (211) had NGS testing first performed during initial disease phase, with a median time from diagnosis of 3.9 years (range, 0-29 years). Sixty-four patients had NGS first performed during the post-ET/post-PV secondary myelofibrosis (SMF) phase, while 19 had NGS first performed during the accelerated phase (AP)/blast phase (BP) of disease. Non-MPN driver mutations were detected in a higher proportion of patients evaluated during disease progression (secondary myelofibrosis or elevated blasts) than during initial disease phase, including more frequent high molecular risk (HMR) mutations (Figure 2). Mutations defined as HMR included pathogenic and likely pathogenic variants in ASXL1, EZH2, IDH1/2, SRSF2, TP53, and U2AF1Q157. Among those patients with NGS testing performed during the initial disease phase, additional mutations were most frequently detected in those with overt PMF (26%).

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